title: Direct in vitro and in vivo comparison of (161)Tb and (177)Lu using a tumour-targeting folate conjugate.
abstract: OBJECTIVE
  The radiolanthanide (161)Tb (T 1/2 = 6.90 days, Eβ(-) av = 154 keV) was recently proposed as a potential alternative to (177)Lu (T 1/2 = 6.71 days, Eβ(-) av = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare (161)Tb and (177)Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09).
  
  
  METHODS
  (161)Tb-cm09 and (177)Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo (161)Tb-cm09 and (177)Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using (99m)Tc-dimercaptosuccinic acid (DMSA).
  
  
  RESULTS
  To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for (161)Tb-cm09 (IC50 ~0.014 MBq/ml and ~2.53 MBq/ml) compared to (177)Lu-cm09 (IC50 ~0.063 MBq/ml and ~4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies (161)Tb-cm09 reduced tumour growth more efficiently than (177)Lu-cm09. These findings were in line with the higher absorbed tumour dose for (161)Tb-cm09 (3.3 Gy/MBq) compared to (177)Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates.
  
  
  CONCLUSIONS
  Compared to (177)Lu-cm09 we demonstrated equal imaging features for (161)Tb-cm09 but an increased therapeutic efficacy for (161)Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of (161)Tb.
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen-PSI, Switzerland, cristina.mueller@psi.ch.
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Josefine
authors.initials: J
authors.lastname: Reber
authors.forename: Stephanie
authors.initials: S
authors.lastname: Haller
authors.forename: Holger
authors.initials: H
authors.lastname: Dorrer
authors.forename: Peter
authors.initials: P
authors.lastname: Bernhardt
authors.forename: Konstantin
authors.initials: K
authors.lastname: Zhernosekov
authors.forename: Andreas
authors.initials: A
authors.lastname: Türler
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
mesh_terms: D000818:Animals; D056831:Coordination Complexes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006367:HeLa Cells; D006801:Humans; D008187:Lutetium / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000532:radiotherapy; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013725:Terbium / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015899:Tomography, Emission-Computed, Single-Photon; D023041:Xenograft Model Antitumor Assays
chemical_list: C000592411:161Tb-cm09; C000592412:177Lu-cm09; D056831:Coordination Complexes; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D013725:Terbium; D008187:Lutetium; D005492:Folic Acid